Our research efforts have been directed towards elucidation of anatomic sites of anesthetic action. Our earlier studies indicated that anesthetics such as isoflurane depress the movement response that occurs following noxious stimulation via an action in the spinal cord. In the past grant cycle we determined that isoflurane and propofol action in the spinal cord depressed the ascending transmission of nociceptive impulses to the brain. This resulted in ablation of the noxious-evoked activation of the electroencephalogram (EEG) and single-units in the thalamus and midbrain reticular formation (MRF). Because the MRF and thalamus are critical to consciousness and memory, it is likely that disruption of nociceptive input to these sites decreases the likelihood of consciousness and memory formation during anesthesia. In this proposal we aim to 1) determine whether isoflurane and propofol action at the spinal level affects the "arousal" state of the brain, as measured by MRF, pedunculopontine tegmental (PPT) and medial thalamic stimulation-induced effects on the EEG; 2) determine the neurotransmitter systems that modulate the ascending transmission of nociceptive impulses to the brain, and how isoflurane and propofol affect these systems. We hypothesize that 1) isoflurane and propofol will increase the threshold stimulation current in the MRF, PPT and medial thalamus required to cause EEG activation; 2) glutamatergic agonists, glycinergic antagonists and GABAergic antagonists applied to the spinal cord will enhance, while glutamatergic antagonists and GABAergic agonists will depress, the ascending transmission of nociceptive impulses to the brain, and thereby cause EEG activation; 3) isoflurane and propofol will indirectly depress evoked glutamate, aspartate and acetylcholine, but enhance GABA concentrations in the cerebral cortex and medial thalamus via an action in the spinal cord. The results of these projects will further our understanding of the in vivo sites where isoflurane and propofol exert their effects. This information will aid the development of newer and safer anesthetics, as well as lead to clinically useful means of modulating the neurotransmitter systems that are themselves modulated by anesthetics.